It is known that 5% of the ethyl alcohol i.e. ethanol (hereinafter alcohol), C2H5OH, ingested by a human being is excreted unchanged while the remaining 95% is degraded to acetaldehyde (hereinafter AcA), CH3CHO, in the cells of alcohol-metabolising tissues, mainly the liver. This reaction (Reaction 1) takes place in the cytoplasm of hepatocytes and is catalysed by the local enzyme alcohol dehydrogenase, ADH. The reaction uses one molecule of the coenzyme nicotinamide-adenine dinucleotide, NAD, per each molecule of alcohol:

During the reaction, NAD and ADH form an enzyme-coenzyme (ADH-NAD) complex, with NAD being concurrently reduced to NADH. The NADH is then detached, and the ADH is ready to repeat the reaction by accepting a new NAD molecule. The cell has a limited capacity to oxidise NADH back to NAD, which determines the maximum velocity of the reaction. A normal liver metabolises alcohol at the rate of about 8 g/h. The rate is independent of the concentration of alcohol in blood. There is an excess of ADH enzyme for the reaction.
The AcA molecules converted from alcohol move into cytoplasmic organelles known as mitochondria where they are oxidised to acetic acid, CH3COOH, in a reaction (Reaction 2) catalysed by the enzyme aldehyde dehydrogenase, ALDH:

In this reaction, too, one molecule of the coenzyme NAD is reduced to NADH. Both the latter and the NADH previously accumulated in the cytoplasm are reoxidised to NAD in the mitochondrial respiratory chain at the maximum capacity of this system. The maximum capacity of the mitochondrial respiratory chain depends on the overall level of metabolism of the body.
The above-described process of alcohol metabolism is illustrated in FIG. 1.
The metabolically harmless acetic acid, derived from alcohol through AcA, is oxidised to carbon dioxide and water mainly in extrahepatic tissues.
The capacity of cells to oxidise NADH back to NAD is exceeded during alcohol degradation according to Reactions 1 and 2. As a result, cells accumulate an excess of NADH compared with NAD. This change in the cellular oxidation-reduction equilibrium, which always takes place in connection with alcohol metabolism, causes inhibition of NAD-mediated enzyme reactions typical to the normal metabolism of the hepatocyte. The most important of these inhibited systems is the citric acid cycle. A positive NADH/NAD ratio, leading to inhibition of the citric acid cycle, is considered the most important reason for the development of alcohol-induced fatty liver.
In a normal liver, 99% of the alcohol brought by blood circulation is metabolised to acetic acid. The remaining 1% is released as AcA into the circulation. So, the capacity of the alcohol-metabolising tissues is not fully sufficient to oxidise all the AcA formed in Reaction 1 to acetic acid according to Reaction 2. This is evident, for instance, from the fact that the venous blood flowing out of the liver during alcohol metabolism carries a 15-μM concentration of AcA (Eriksson and Fukunaga 1992).
The acute toxicity of AcA (mouse LD100=0.75 g/kg) is severalfold compared with that of alcohol (mouse LD70=6.5 g/kg).
As explained above, during alcohol use about 1% of AcA normally “escapes” Reaction 2 in the liver and enters the blood circulation at the rate of about 1 mg/min (60 mg/h). If the alcohol consumption is sufficient to maintain a concentration of alcohol in blood for 24 hours (200 g of alcohol is enough, i.e. the amount contained in a half-liter of distilled spirit), the amount of AcA released into the circulation is on average 1.5 g. As a single dose, this amount of AcA would be enough to kill 100 mice each weighing 20 g.
Still larger amounts of AcA than those mentioned above are released into the blood circulation in case of impaired ALDH activity. A reduction as small as 10% in the capacity of hepatic ALDH triples the amount of AcA leaked into the circulation.
ALDH can be inhibited by certain drugs, such as disulfiram (Antabuse®). In a person on disulfiram therapy, ingestion of a few grams of alcohol will produce very unpleasant symptoms lasting up to several hours. The symptoms include headache and a flushed skin. Dyspnoea and nausea are also common, as are tachycardia and hypotension. The symptoms are due to AcA accumulation in the body.
Heavy use of alcohol is followed by hangover, a familiar consequence of alcohol intoxication. A person fearing hangover may seek to prolong his/her use of alcohol. The fact that efforts to develop an adequate pharmacological means of treating hangover have so far been unsuccessful may also contribute to such behaviour. Alleviation of hangover has been attempted by vitamins and trace elements (cf. U.S. Pat. No. 4,496,548). A major part of hangover symptoms may be due to the toxic effects of AcA.
Biochemical and medical research suggests a major role for AcA in the development of alcohol dependence. These conclusions are based on the changes that AcA induces in the structures of cerebral neurotransmitters. AcA has also been found to inhibit enzymes involved in protein synthesis and to alter the immunological properties of tissues. Through such mechanisms, AcA may in fact play a more significant role than alcohol in the aetiology of many alcohol-related diseases, such as brain damage and hepatic cirrhosis and also compulsive drinking itself.
As explained above, it has become clear that elevation of the NADH/NAD ratio, which suppresses normal metabolism in alcohol-metabolising tissues, and the release and accumulation of AcA in the systemic circulation and thereby in the entire body are major mechanisms in the development of alcohol-related health problems.
In view of the above-mentioned facts, AcA-binding compounds have been deployed to reduce the amount of AcA released into the systemic circulation and to lessen the consequences of such release. These compounds include the sulphur-containing amino acids cysteine and methionine. Oral administration of methionine to experimental subjects during alcohol drinking has yielded 20% reductions in blood AcA concentrations (Tabakoff et al. 1989). It should be noted, however, that methionine-bound AcA may later detach, thus obliterating the minor benefit achieved. Furthermore, methionine and other similar substances do not affect the rate of alcohol metabolism, nor the NADH/NAD ratio.
In addition to the above-mentioned methods, it has been proposed that the adverse health effects of alcohol might be reduced with agents that modify the rate of alcohol metabolism:
Both the amount of AcA released from the liver and the NADH/NAD ratio can be lowered by 4-methylpyrazole, 4-MP. This is an ADH inhibitor which slows down Reaction 1 (see page 1). As a result, the production of AcA is reduced and, with less substrate, Reaction 2 becomes more effective allowing more extensive conversion of AcA to acetic acid. Owing the diminished total capacity of the reactions, there is no intracellular accumulation of NADH. 4-MP is useful in special circumstances requiring deceleration of alcohol metabolism, e.g. in the management of methanol poisoning. 4-MP is not suited to addressing the aforementioned problem of AcA accumulation. Because of its decelerating effect on alcohol elimination, it would be impossible to use in conjunction with conventional alcohol drinking (risk of alcohol poisoning).
The accelerating effect of fructose on the rate of alcohol elimination has been known for a long time (Crownover et al. 1986). The elimination rate may be enhanced by up to 20% but this requires large doses (1-5 g/kg) to be taken together with the alcohol. Trials have been conducted of the prevention of hangover symptoms by means of fructose, without tangible benefit. It has been established that acceleration of alcohol metabolism by fructose is effected specifically through Reaction 1. This method of increasing the rate of alcohol metabolism leads to the formation of a corresponding amount of AcA which the cell is unable to metabolise to acetic acid. This is reflected as a corresponding elevation of AcA concentration in the blood flowing out of the liver (Eriksson and Fukunaga 1992).
It has also been known for a long time that D-glyceraldehyde (hereinafter D-GA; see FIG. 3, “Metabolism of fructose”, (Harper et al. 1977)), a metabolite of fructose, has an accelerating effect on alcohol metabolism (Thieden et al. 1972). The effect of D-GA on the metabolism of AcA is similar to that of fructose, in that the accelerating effect on alcohol metabolism takes place via Reaction 1 and not via Reaction 2. Akin to fructose, D-GA therefore tends to cause AcA accumulation.
U.S. Pat. No. 4,450,153 presents a solution whereby blood alcohol concentration can be rapidly reduced using an alcohol oxidase enzyme isolated from certain species of yeast. Said enzyme degrades alcohol to AcA in the extracellular space. This causes large amounts of AcA to enter the blood circulation and, consequently, a risk of AcA poisoning.
The present invention offers substantial remediation of the shortcomings presented above.